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| United States Patent |
5,698,707
|
|
Griffiths
, et al.
|
December 16, 1997
|
Process for the preparation of optionally 2-substituted
5-chloroimidazole-4-carbaldehydes
Abstract
A process for the preparation of 2-substituted
5-chloroimidazole-4-carbaldehydes of the general formula:
##STR1##
wherein R is hydrogen, an alkyl group, an alkenyl group, a cycloalkyl
group, a benzyl group or a phenyl group. The imidazole compounds are
important starting products for the preparation of hypotensive
pharmaceuticals or herbicides.
| Inventors:
|
Griffiths; Gareth (Visp, CH);
Stucky; Gerhard (Brig-Glis, CH)
|
| Assignee:
|
Lonza Ltd. (Gampel/Valais, CH)
|
| Appl. No.:
|
644249 |
| Filed:
|
May 10, 1996 |
Foreign Application Priority Data
| Current U.S. Class: |
548/333.5 |
| Intern'l Class: |
C07D 233/64 |
| Field of Search: |
548/333.5
|
References Cited
U.S. Patent Documents
| 4345935 | Aug., 1982 | Thibault | 71/92.
|
| 4355040 | Oct., 1982 | Furukawa et al. | 424/273.
|
| 5395943 | Mar., 1995 | Yamamoto et al. | 548/333.
|
| 5442076 | Aug., 1995 | Gosteli et al. | 548/333.
|
| 5486617 | Jan., 1996 | Griffiths et al. | 548/333.
|
| 5508425 | Apr., 1996 | Griffiths et al. | 548/343.
|
| 5565577 | Oct., 1996 | Mokhallalati et al. | 548/333.
|
| Foreign Patent Documents |
| 0579212 | Jan., 1994 | EP.
| |
| 0 614 890 A2 | Sep., 1994 | EP.
| |
| 0614890 | Sep., 1994 | EP.
| |
| 0614892 | Sep., 1994 | EP.
| |
| 0653422 | May., 1995 | EP.
| |
| 2804435 | Aug., 1978 | DE.
| |
Other References
Watson, A convenient synthesis of
2-butyl-4(5)-chloro-1H-imidazole-5(4)carboxaldehyde, Synthetic
Communications, 22(20), pp. 2971-2977 (1992).
|
Primary Examiner: Shah; Mukund J.
Assistant Examiner: Rao; Deepak R.
Attorney, Agent or Firm: Fisher, Christen & Sabol
Claims
What is claimed is:
1. A process for the preparation of an optionally 2-substituted
5-chloroimidazole-4-carbaldehyde of the formula:
##STR11##
wherein R is hydrogen, alkyl, alkenyl, cycloalkyl, benzyl or phenyl,
comprising: reacting an optionally 2-substituted 5-chloroimidazole of the
formula:
##STR12##
wherein R has the above-described meaning, with an amine of the formula:
##STR13##
wherein R.sub.1 and R.sub.2 are identical or different and each is
(C.sub.1 -C.sub.6)-alkyl or R.sub.1 and R.sub.2 together form a (C.sub.2
-C.sub.3)-alkylene bridge, R.sub.3 and R.sub.4 are identical or different
and each is (C.sub.1 -C.sub.6)-alkyl or R.sub.3 and R.sub.4 together with
the amine nitrogen form a 5- or 6-membered saturated heterocycle, which
can contain oxygen or nitrogen as an additional hetero atom, to give an
optionally 2-substituted 5-chloroimidazol-4-ylidenemethylamine of the
formula:
##STR14##
wherein R, R.sub.3, and R.sub.4 have the above-described meanings; and the
optionally 2-substituted 5-chloroimidazol-4-ylidenemethylene of formula IV
is finally hydrolyzed to give the optionally 2-substituted
5-chloroimidazole-4-carbaldehyde of formula I.
2. The process according to claim 1 wherein the process is carried out in
the presence of a tertiary amine as a base.
3. The process according to claim 2 wherein the
2-substituted-5-chloroimidazol-4-ylidenemethylamine of formula IV is not
isolated before being hydrolyzed.
4. The process according to claim 3 wherein the reaction with the amine of
formula III is carried out at a temperature between 20.degree. and
200.degree. C. in the presence of an inert solvent.
5. The process according to claim 1 wherein the
2-substituted-5-chloroimidazol-4-ylidenemethylamine of formula IV is not
isolated before being hydrolyzed.
6. The process according to claim 1 wherein the reaction with the amine of
formula III is carried out at a temperature between 20.degree. and
200.degree. C. in the presence of an inert solvent.
7. The process according to claim 1 wherein R is 2-butenyl, 3-butenyl,
n-propyl or n-butyl.
8. The process according to claim 1 wherein R.sub.1, R.sub.2, R.sub.3 and
R.sub.4 are each methyl or ethyl.
9. The process according to claim 2 wherein the tertiary amine is employed
in an amount of 0.05 to 2 molar equivalents, based upon 1 mol of
2-substituted 5-chloroimidazole of formula II.
10. The process according to claim 1 wherein the reaction with the amine of
formula III is carried out at a temperature between 100.degree. and
150.degree. C. in the presence of an inert solvent.
11. The process according to claim 10 wherein the inert solvent is
chlorobenzene or toluene.
12. The process according the claim 1 wherein R is selected from the group
consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,
tert-butyl, n-pentyl, an isomer of n-pentyl, n-hexyl and an isomer of
n-hexyl.
13. The process according to claim 1 wherein R.sub.1 and R.sub.2 are
identical or different and each of R.sub.1 and R.sub.2 is selected from
the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl,
sec-butyl, tert-butyl, n-pentyl, an isomer of n-pentyl, n-hexyl and an
isomer of n-hexyl.
14. The process according to claim 13 wherein R.sub.1 and R.sub.2 are
identical.
15. The process according to claim 1 wherein R.sub.1 and R.sub.2 form an
ethylene bridge.
16. The process according to claim 1 wherein R.sub.3 and R.sub.4 are
identical or different and each of R.sub.1 and R.sub.2 is selected from
the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl,
sec-butyl, tert-butyl, n-pentyl, an isomer of n-pentyl, n-hexyl and an
isomer of n-hexyl.
17. The process according to claim 16 wherein R.sub.3 and R.sub.4 are
identical.
18. The process according to claim 1 wherein R.sub.3 and R.sub.4 form an
ethylene bridge.
19. The process according to claim 1 wherein R.sub.3 and R.sub.4 together
with the amine nitrogen of formula III form a 5- or 6-member saturated
heterocycle, which can contain oxygen or nitrogen as an additional hetero
atom.
20. The process according to claim 19 wherein the 5- or 6-member saturated
heterocycle is a pyrrolidine ring, a piperazine ring, a piperidine ring or
a morpholine ring.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention involves a novel process for the preparation of 2-substituted
5-chloroimidazole-4-carbaldehydes of the general formula:
##STR2##
in which R denotes hydrogen, an alkyl group, an alkenyl group, a
cycloalkyl group, a benzyl group or a phenyl group.
2. Background Art
A number of ways are known for the preparation of the compounds according
to general formula I.
Thus, U.S. Pat. No. 4,355,040 describes a process by which
2-amino-3,3-dichloroacrylonitrile is reacted with an aldehyde to give the
corresponding azomethine intermediate, which is further reacted with a
hydrogen halide and water to give the 2-substituted
5-haloimidazole-4-carbaldehyde. There are no experimental data given in
the patent. A great disadvantage of the synthesis is that the
2-amino-3,3-dichloroacrylonitrile used must first be prepared starting
from dichloroacetonitrile, by its reaction with hydrogen cyanide/sodium
cyanide. The extremely toxic reactants and the safety precautions
associated therewith, which are necessary even for the preparation of the
starting product, make the overall process industrially unsuitable.
U.S. Pat. No. 4,355,040 discloses, in a further variant, a 3-stage process,
in which, in a first stage, an amidine hydrochloride is cyclized with
dihydroxyacetone at high NH.sub.3 pressure, the imidazole alcohol is
halogenated and is finally oxidized to the aldehyde. It was shown that
pressures of greater than 20 bar are necessary for the ring-closure
reaction.
The oxidation of the alcohol functions, according to U.S. Pat. No.
4,355,040, in the presence of chromium oxide. It is obvious that oxidation
with heavy metal oxides, which are generally not able to be recirculated,
is no longer justifiable from current ecological viewpoints.
BROAD DESCRIPTION OF THE INVENTION
The main object of the invention is to provide a process which does not
have the above-described disadvantages of the prior art. Other objects and
advantages of the invention are set out herein or are obvious herefrom to
one skilled in the art.
The process and intermediate compounds of the invention achieve the objects
and advantages of the invention.
The invention involves a process for the preparation of optionally
2-substituted 5-chloroimidazole4-carbaldehydes of the general formula:
##STR3##
in which R denotes hydrogen, an alkyl group, an alkenyl group, a
cycloalkyl group, a benzyl group or a phenyl group. The process includes
reacting an optionally 2-substituted 5-chloroimidazole of the general
formula:
##STR4##
in which R has the above-described meaning, with an amine of the general
formula:
##STR5##
in which R.sub.1 and R.sub.2 are identical or different and denote a
(C.sub.1 -C.sub.6)-alkyl group or R.sub.1 and R.sub.2 together form a
(C.sub.2 -C.sub.3)-alkylene bridge, R.sub.3 and R.sub.4 are identical or
different and denote a (C.sub.1 -C.sub.6)-alkyl group or R.sub.3 and
R.sub.4 together with the amine nitrogen form a 5- or 6-membered saturated
heterocycle, which may contain oxygen or nitrogen as an additional hetero
atom, to give an optionally 2-substituted
5-chloroimidazol-4-ylidenemethylamine of the general formula:
##STR6##
in which R, R.sub.3 and R.sub.4 have the above-described meanings.
Finally, the amine of general formula IV is hydrolyzed to give the end
product.
Preferably, the invention process is carried out in the presence of a
tertiary amine as a base. Preferably, the 2-substituted
5-chloroimidazol-4-ylidenemethylamine of general formula IV is not
isolated before it is hydrolyzed. Preferably, the reaction with the amine
of general formula III is carried out at a temperature between 20.degree.
and 200.degree. C. in the presence of an inert solvent.
The invention also involves 2-substituted
5-chloroimidazol-4-ylidenemethylamines of the general formula:
##STR7##
in which R, R.sub.3 and R.sub.4 have the above-described meanings.
Preferably, the amine of general formula IV is
(2-n-butyl-5-chloroimidazol-4-ylidenemethyl)-dimethylamine, or
(2-n-butyl-5-chloroimidazol-4-ylidenemethyl)diethylamine, or
(2-n-propyl-5-chloroimidazol-4-ylidenemethyl)dimethylamine, or
(2-n-propyl-5-chloroimidazol-4-ylidenemethyl)diethylamine.
The 2-substituted 5-chloroimidazole-4-carbaldehydes of general formula I
are important starting products for the preparation of hypotensive
pharmaceuticals (U.S. Pat. No. 4,355,040) or of herbicidally active
compounds (DE-A 2804435).
DETAILED DESCRIPTION OF THE INVENTION
According to the invention, an optionally 2-substituted 5-chloroimidazole
of the general formula:
##STR8##
in which R has the above-described meaning, is first reacted with an amine
of the general formula:
##STR9##
in which R.sub.1 and R.sub.2 are identical or different and denote a
(C.sub.1 -C.sub.6)-alkyl group or R.sub.1 and R.sub.2 together form a
(C.sub.2 -C.sub.3)-alkylene bridge, R.sub.3 and R.sub.4 are identical or
different and denote a (C.sub.1 -C.sub.6)-alkyl group or R.sub.3 and
R.sub.4 together with the amine nitrogen form a 5- or 6-membered saturated
heterocycle, which may contain oxygen or nitrogen as an additional hetero
atom, to give an optionally 2-substituted
5-chloroimidazol-4-ylidenemethylamine of the general formula:
##STR10##
in which R, R.sub.3 and R.sub.4 have the above-described meaning. The
amine of general formula IV is then hydrolyzed to provide the end product
of the general formula I.
R in the meaning of alkyl represents straight-chain or branched C.sub.1
-C.sub.6 -alkyl, such as, methyl, ethyl, propyl, isopropyl, n-butyl,
sec-butyl, tert-butyl, pentyl and its isomers or hexyl and its isomers. A
preferred alkyl for R is n-propyl or n-butyl. R in the meaning of alkenyl
represents straight-chain or branched C.sub.1 -C.sub.6 -alkenyl, such as,
1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, pentenyl and its
isomers or hexenyl and its isomers. A preferred alkenyl for R is 2- or 3-
butenyl. Representatives of cycloalkyl are cyclopropyl, cyclobutyl,
cyclopentyl, and cyclohexyl. Both benzyl and phenyl can carry
substituents, such as, halo, nitro, amino and said alkyls.
The term halogen (halo) is expediently understood to include fluorine
(fluoro), chlorine (chloro), bromine (bromo) and iodine (iodo), preferably
chlorine (chloro).
The 2-substituted 5-chloroimidazole of general formula II as a starting
compound for the process of the invention is accessible by chlorination of
the corresponding 3,5-dihydroimidazol-4-one according to European
Published Patent Application No. A 0,614,890.
Suitable amines of general formula III are those in which R.sub.1 and
R.sub.2 have the identical meaning and denote C.sub.1 -C.sub.6 -alkyl,
such as, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,
pentyl and its isomers or hexyl and its isomers, or in which R.sub.1 and
R.sub.2 together form an ethylene bridge and in which R.sub.3 and R.sub.4
have the identical meaning and represent one of the said C.sub.1 -C.sub.6
-alkyl groups.
R.sub.3 and R.sub.4 together with the amine nitrogen can also form a 5- or
6-membered saturated heterocycle, which can contain oxygen or nitrogen as
an additional hetero atom. Therefore, R.sub.3 and R.sub.4 together with
the amine nitrogen can form a pyrrolidine ring, a piperazine ring, a
piperidine ring or a morpholine ring. Preferably, R.sub.1, R.sub.2,
R.sub.3 and R.sub.4 represent methyl or ethyl.
Particularly suitable amines of general formula III are
dimethoxymethyldimethylamine and diethoxymethyldiethylamine.
The amines of general formula III are expediently used in an amount of 1 to
5 molar equivalents, preferably 1 to 2 molar equivalents, based on 1 mol
of 2-substituted 5-chloroimidazole of general formula II.
A selective reaction to give the optionally 2-substituted
5-chloroimidazole-4-ylidenemethylamine of general formula IV can be
achieved if the procedure is carried out in the presence of a tertiary
amine as a base. Expediently, the tertiary amine is employed in an amount
of 0.05 to 2.0 molar equivalents, based on 1 mol of the 2-substituted
5-chloroimidazole of general formula II. Preferably, a trialkylamine, such
as, triethylamine, is used. The reaction with the amine of general formula
Ill expediently proceeds at a temperature between 20.degree. and
200.degree. C., preferably at a temperature of 100.degree. to 150.degree.
C., in the presence of an inert solvent. Although lower temperatures are
possible, they retard the reaction and promote side reactions. Suitable
solvents which have proved useful are higher-boiling aromatics, such as,
chlorobenzene or toluene.
The resulting optionally 2-substituted
5-chloroimidazol-4-ylidenemethylamines of general formula IV are not
disclosed in the literature and form an essential constituent of the
invention as a central intermediate of the process of the invention.
Particularly preferred compounds of general formula IV are
(2-butyl-5-chloroimidazol-4-ylidenemethyl)dimethylamine (R is n-butyl, and
each of R.sub.3 and R.sub.4 is methyl),
(2-butyl-5-chloroimidazol-4-ylidenemethyl)diethylamine (R is n-butyl, and
each of R.sub.3 and R.sub.4 is ethyl),
(2-n-proypl-5-chloroimidazol-4-ylidenemethyl)dimethylamine (R is n-propyl,
and each of R.sub.3 and R.sub.4 is methyl) and
(2-n-propyl-5-chloroimidazol-4-ylidenemethyl)diethylamine (R is n-propyl,
and each of R.sub.3 and R.sub.4 is ethyl).
Generally, the compounds of general formula IV are not isolated in the
course of the process, but are directly hydrolyzed to give the end
product.
The hydrolysis conditions are not critical, that is the hydrolysis can
proceed in acidic, alkaline or neutral conditions.
The resulting 2-substituted 5-chloroimidazole-4-carbaldehyde can be
isolated in a manner conventional for those skilled in the art, generally
by extraction from the aqueous reaction mixture with a suitable solvent.
EXAMPLE 1
(a) Preparation of (2-n-butyl-5-chloroimidazol-4-yl-idenemethyl)
dimethylamine
A solution of 2-n-butyl-5-chloro-1H-imidazole (0.79 g, 5 mmol) and
dimethoxymethyldimethylamine (0.80 g, approximately 92 percent pure, 6.2
mmol) in chlorobenzene (20 ml) was heated for 1.5 hours at 130.degree. C.
10 ml of the reaction solution was evaporated to dryness and dried under
high vacuum. The dark-brown oil (0.46 g) thusly obtained contained the
title compound (approximately 80 percent pure according to H--NMR); this
corresponded to a yield of approximately 70 percent, based on the starting
2-n-butyl-5-chloro-1 H-imidazole. Data concerning the product is:
.sup.1 H--NMR (400 MHz, CDCl.sub.3);.delta. 0.92 (3H, t)
1.42 (2H, m),
1.74 (2H, m),
2.71 (2H, t),
3.36 (3H, s),
3.80 (3H, s),
7.37 (1H, s).
MS; 213 (M.sup.+), 171 (M-42) (100%).
(b) Preparation Of (5-chloro-2-propylimidazol-4-ylidenemethyl)
dimethylamine
A solution of 5-chloro-2-propyl-1H-imidazole (0.72 g, 5 mmol),
dimethoxymethyldimethylamine (0.77 g, approximately 92 percent pure, 6
mmol) and triethylamine (0.10 g, 1 mmol) in chlorobenzene (25 ml) was
heated for 1 hour at 60.degree. C. and for 2 hours under reflux. Removing
the solvent in a rotavapor gave the title compound in virtually
quantitative yield. Data concerning the product was:
.sup.1 H--NMR (400 MHz, CDCl.sub.3); .delta. 0.96 (3H, t),
1.78 (2H, m),
2.60 (2H, t),
3.39 (3H, s),
3.80 (3H, s),
7.38 (1H, s).
MS; 199 (M.sup.+), 171 (M-28) (100%).
EXAMPLE 2
(a) Preparation of 2-n-butyl-5-chloroimidazole-4-carbaldehyde (solvent:
chlorobenzene)
A solution of 2-n-butyl-5-chloro-1H-imidazole (1.59 g, 10 mmol),
dimethoxymethyldimethylamine (1.94 g, approximately 92 percent pure, 15
mmol) and triethylamine (0.10 g, 1.0 mmol) in chlorobenzene (44 ml) was
heated for 2.5 hours at 130.degree. C., cooled to 30.degree. C. and poured
into 2N HCl (50 ml). The mixture was stirred for 0.5 hour at room
temperature and was adjusted from pH -0.34 to pH 1.20 by addition of 30
percent strength sodium hydroxide solution (8.9 ml). The phases were
separated and the aqueous phase was extracted twice, each time with 30 ml
of ethyl acetate. The combined organic phases were dried (MgSO.sub.4),
filtered, concentrated and dried at high vacuum. The solid (1.67 g) thusly
obtained contained the title compound (approximately 75 percent pure
according to H--NMR); this corresponded to a yield of approximately 67
percent, based on the starting 2- n-butyl-5-chloro-1H-imidazole. Other
data concerning the product was:
.sup.1 H--NMR (400 MHz, CDCl.sub.3);.delta. 0.93, (3H, t),
1.42(2H, m),
1.75(2H, m),
2.82(2H, t),
9.61(1H, s),
11.38 (1H, br. s).
(b) Preparation of 2-n-butyl-5-chloroimidazole-4-carbaldehyde (solvent:
toluene)
A solution of 2-n-butyl-5-chloro-1H-imidazole (1.59 g, 10 mmol),
dimethoxymethyldimethylamine (1.94 g, approximately 92 percent pure, 15
mmol) and triethylamine (0.10 g, 1.0 mmol) in toluene (35 ml) was heated
for 4.5 hours at 110.degree. C., cooled to 30.degree. C. and poured into
2N HCl (50 ml). The mixture was stirred for 0.5 hour at room temperature
and was adjusted from pH -0.28 to pH 1.20 by addition of 30 percent
strength sodium hydroxide solution (8.7 ml). The phases were separated and
the aqueous phase was extracted twice, each time with 30 ml of ethyl
acetate. The combined organic phases were dried (MgSO.sub.4), filtered,
concentrated and dried at high vacuum. The solid (1.64 g) thusly obtained
contained the title compound (approximately 80 percent pure according to
H--NMR); this corresponded to a yield of approximately 70 percent, based
on the starting 2-n-butyl-5-chloro-1H-imidazole.
(c) Preparation of 2-propyl-5-chloroimidazole-4-carbaldehyde
A solution of 5-chloro-2-propyl-1H-imidazole (1.45 g, 10 mmol),
dimethoxymethyldimethylamine (1.55 g, approximately 92 percent pure, 12
mmol) and triethylamine (0.10 g, 1 mmol) in chlorobenzene (50 ml) was
heated for 1 hour at 80.degree. C. and 2.5 hours under reflux, cooled to
room temperature and poured into 2M hydrochloric acid (100 ml). The pH was
adjusted to pH 1.97 by addition of 30 percent strength sodium hydroxide
solution (19 ml) and the mixture was extracted three times, each time with
50 ml of ethyl acetate. The combined organic phases were dried and
concentrated on a rotavapor. The yield of the product was 1.27 g
(approximately 90 percent pure according to H--NMR), 66 percent based on
5-chloro-2-propyl-1H-imidazole. Other data concerning the product was:
.sup.1 H--NMR (400 MHz, CDCl.sub.3); .delta. 1.01 (3H, t),
1.84(2H, m),
2.83(2H, t),
9.64(1H, s),
11.56(b. s, 1H).
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